1. Field of the Invention
The present invention is directed to methods and pharmaceutical compositions for differentially reducing, inhibiting or preventing the increase in gene expression caused by neurological disorders to precondition, treat and/or provide neuroprotection to the animal central nervous system against ischemia, neurodegeneration, metal poisoning and trauma, including associated cognitive, behavioral and physical impairments.
2. Description of the Related Art
Certain medical procedures, for example coronary artery bypass graft (CABG) surgery, are associated with neurological complications. In the case of CABG, the surgery is performed on more than 800,000 patients worldwide each year. Many of the CABG procedures performed are associated with neurological complications. These complications range from stroke in up to 16% of the patients to general cognitive decline with 50% of patients having impairment post-surgery and with progressive decline occurring in some patients over the next five years. In addition, physical and behavioral impairment manifest in some CABG patients. Newman M F et al., N. Eng. J. Med. 344:395-402 (2001); Brillman J., Neurol. Clin. 11:475-495 (1993); and Selnes, O. A., Ann. Thorac. Surg. 67:1669-1676 (1999) are instructive.
Originally, it was hypothesized that the neurological complications associated with CABG surgery were either procedure or patient-related. The procedure generally implicated as potentially harmful was cardiopulmonary bypass using a pump and oxygenator. However, a recent study reports no difference in cognitive outcome between groups of patients undergoing CABG surgery performed with, or without, the pump and oxygenator. Such results suggest that the neurological impairments following CABG surgery may, in fact, be patient-related and, as a result, amenable to therapeutic manipulation.
In addition, patients at risk for, or diagnosed with disorders involving neurological impairments, e.g., Alzheimer's disease (AD), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), and spinal cord injury may benefit from similar therapeutic manipulation. See Crapper Mclachlan, D. R., Dalton, A. J., Kruck, T. P. A., Bell, M. Y., Smith, W. L., Kalow, W., and Andrews, D. F. Instramuscular desferrioxamine in patients with Alzheimer's disease. The Lancet 337:1304-1308, 1991.
A number of neurodegenerative disorders are known to have metal-associated pathology, i.e., resulting at least in part from metal poisoning, and may benefit from the therapeutic manipulation contemplated by embodiments of the present invention. These include AD, PD, Creutzfeldt-Jakob disease, familial amyotrophic lateral sclerosis, lewy-body dementia, carotid atherosclerosis, tardive dyskinesia, multiple sclerosis, Wilson's disease, progressive supranuclear palsy, Hallervorden-Spatz syndrome, multisystem atrophy, Huntington's disease, familial basal ganglia degeneration, Down's syndrome, cataracts, haemochromatosis, cerebral haemorrhage and head injury. See P. M. Doraiswamy and A. E. Finefrock, Metals in our minds: therapeutic implications for neurodegenerative disorders, The Lancet Neurology, Vol. 3, July 2004.
In general, ischemic conditions activate a number of genes that are important in cellular and tissue adaptation to low oxygen conditions. These genes include erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor (VEGF). VEGF is a major angiogenic factor that has been shown to activate new blood vessel formation. Transcriptional up-regulation has been shown to be implicated in the induction of the VEGF gene, an action mediated by the specific binding of the hypoxia-inducible factor-1 (HIF-1) to the hypoxic response element (HRE).
In addition, caspase molecules, e.g., those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -3, -6, -7, -8, -9, -10, and -12), mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Caspase-12 has been shown to be a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta toxicity, suggesting that, inter alia, caspase-12 may contribute to the pathogenesis of Alzheimer's disease. See, e.g., Saleh M Vaillancourt J P, et al., Differential Modulation of Endotoxin Responsiveness by Human Caspase-12 Polymorphisms, Nature, 2004 May 6; 429 (6987): 75-9. In addition, caspases, e.g., caspase-4 and caspase-12, are present in elevated concentrations following stroke. Therefore, a therapeutic treatment that inhibits, reduces or prevents cell death and inflammation, resulting, in turn, inhibits, reduces or prevents the expression of genes for caspases would be helpful in preventing and/or minimizing certain effects of, inter alia, stroke and/or Alzheimer's disease, as well as pretreating these conditions to minimize the effects of such disorders.
It is further known that expression of the gene for matrix metallopeptidase-9 (MMP9) is increased during and after a stroke. MMP9 is involved in apoptosis and has been linked to an increased risk for hemorrhagic transformation following ischemic episodes such as stroke. In addition, MMP9 has been linked to increased brain swelling (inflammation) and cellular damage after a stroke. Therefore, a therapeutic treatment that inhibits, reduces or prevents cell death and inflammation and, in turn, reducing, inhibiting or preventing the expression of genes for MMP9 would be helpful in preventing and/or minimizing certain effects of, inter alia, stroke and/or Alzheimer's disease, as well as in pretreating to minimize the effects of such disorders.
Expression of the gene for annexin-A1 is increased during and after stroke or ischemic episode. It is known that expression of annexin-A1 increases in response to inflammation, therefore, a therapeutic treatment that inhibits, reduces or prevents inflammation, e.g., brain inflammation, resulting in the inhibition, reduction or prevention of expression of the gene for annexin-A1, may be helpful in preventing certain effects of, inter alia, stroke, as well as in pretreating to minimize the effects of such disorders.
The gene for heme oxygenase (decycling)-1 is known to increase expression during and after stroke and in response to oxidative stress in stroke and other central nervous system disorders such as Alzheimer's disease. Therefore, a therapeutic treatment that inhibits, reduces or prevents oxidative stress as evidenced by the inhibited, reduced or prevented expression of heme oxygenase (decycling)-1, may be helpful in preventing certain effects of, inter alia, stroke, as well as in pretreating to minimize the effects of such disorders.
Expression of the gene for insulin-like grown factor-2 (IGF-2) is increased during and following stroke. IGF-2, administered intracerebroventricularly following hypoxia/ischemia has been shown to cause neurodegenerative effects, including inter alia, an increase neuronal loss in the hippocampus and dentate gyrus. Moreover, IGF-2 has been shown to block the neuroprotective effects of IGF-1. Therefore, a therapeutic treatment that inhibits, prevents or reduces these neurodegenerative effects, as evidenced by the reduced expression of IGF-2, may be helpful in inhibiting, reducing or preventing certain effects of, inter alia, stroke, Alzheimer's disease and other central nervous system disorders, as well as in pretreating to minimize the effects of such disorders.
The HIF-1 transcription factor is a heterodimer composed of HIF-1α and HIF-1β and regulates the adaptive response to hypoxia in animal cells. HIF-1α accumulates under hypoxic conditions, but is virtually undetectable in normal oxygen conditions. HIF-1β, on the other hand, is readily found in all cells. The HIF-1 heterodimer is believed to be neuroprotective against ischemia through the activation of EPO and VEGF.
HIF-1α has been shown in vitro to be activated by metal chelators, including both iron and copper chelating agents. A particular example of such an agent is deferoxamine (DFO), a hexadentate iron chelator, with kinetics similar to those associated with hypoxia, resulting in increased expression of HIF-1 target genes, including EPO and VEGF. Other examples of iron chelators are deferasirox and deferiprone. DFO is also known to stabilize HIF-1 subunits, possibly by chelating and inactivating the iron that plays a role in targeting the subunit for proeolytic degradation under normoxic conditions.
In vivo studies have demonstrated that DFO induces HIF-1α in neonatal and adult rats, injecting the chelator either subcutaneously (s.c.) or intraperitoneally (i.p.), typically in very high dosage. In addition, studies indicate that the following substances stimulate and/or stabilize HIF-1α: insulin, IGF-I, heregulin, TGFbeta, IL-1beta, TNFalpha, cobalt, pyruvate, oxalacetate and lactate.
Problems exist, however, with the administration of DFO intravenously. DFO is not generally injected intravenously for at least two reasons. First, it is a small molecule and, as a result, is eliminated rapidly through the kidney. The typical plasma half-life in humans is less than 10 minutes. Second, the injection of an intravenous bolus of DFO causes acute hypotension that is rapid, may lead to shock and may be lethal. These characteristics have limited the utility of DFO in particular as a neuroprotective agent.
One published study administered DFO intranasally to iron overloaded patients. G. S. Gordon et al., Intranasal Administration of Deferoxamine to Iron Overloaded Patients, (1989) Am. J. Med. Sci. 297(5):280-284. In this particular study, DFO was administered to the patients as a nasal spray in a volume of 75 microliters per spray. Significantly, such sprays are known to deposit the drug or other substance in the lower third of the nasal cavity. This is verified by patient observations stating that a bad taste in the mouth was resulting from the drug passing through the nasopharynx and into the mouth. As a result, this study did not involve delivering the drug to the upper third of the nasal cavity. Thus, the drug would not have reached the olfactory epithelium or the olfactory nerves. As a result, delivery of the drug to the CNS would be less than optimal.
It is recognized that intranasal delivery to the CNS may occur along both the olfactory and trigeminal nerve pathways. See Thorne, R G (2004), Delivery of Insulin-Like Growth Factor-I to the Rat Brain and Spinal Cord Along Olfactory and Trigeminal Pathways Following Intranasal Administration, Neuroscience, Vol. 127, pp. 481-496. Optimal delivery taking advantage of both pathways is accomplished by administering the substance in the upper third of the nasal cavity.
Regarding Alzheimer's disease, some studies indicate that cerebral vascular problems occur first, followed by neurodegeneration in later stages of the disease. For example, see The Lancet Neurology, vol. 3, page 184-190, Jack C. de la Torre (March, 2004). Thus, it may be possible to prevent, mitigate or treat the effects of Alzheimer's disease at the appropriate disease stage through therapeutic manipulation targeted toward mitigation or prevention of cerebral ischemia or neurodegeneration.
In a published patent application, U.S. Pat. App. No. 20020028786 by William H. Frey II (also a co-inventor of the present application) entitled METHODS AND COMPOSITIONS FOR ENHANCING CELLULAR FUNCTION THROUGH PROTECTION OF TISSUE COMPONENTS, various substances are discussed that may be administered intranasally to treat various diseases and conditions. The entire contents of this reference are hereby incorporated by reference.